The long-term objective of this project is to understand the mechanisms underlying synaptic dysfunction in neurodegenerative diseases. Synaptic dysfunction is an early hallmark of neurodegenerative diseases, preceding neuronal death and the onset of clinical symptoms. However, how synaptic deterioration relates to later stages of disease progression is unclear. Evidence suggests that synaptic dysfunction is reversible and can delay cell death, highlighting the need for understanding synaptic pathology and it's role in neurodegenerative diseases. We seek to address this issue using Drosophila to analyze the structural and functional integrity of synapses prior to and during neurodegeneration. We will focus on the neuromuscular junctions (NMJs) innervating the dorsal longitudinal flight muscles to examine this synaptic pathology. We plan to analyze synapses using established models of neurodegeneration, including expression of toxic proteins implicated in neurodegenerative diseases, as well as Drosophila neurodegeneration mutants. This analysis will address three questions: 1) How are synapses impaired prior to the onset of degeneration? 2) Does synaptic dysfunction cause neurodegeneration? 3) Does reversing this dysfunction prevent neuronal death? We also plan to identify novel genes involved in synaptic dysfunction and neurodegeneration using RNAi transgenes, and characterize their roles in degeneration. This research will help us to understand early stages of disease progression, broadening our understanding of neuronal death and allowing development of therapeutic targets to treat neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: Much progress has been made on understanding the nature of neurodegenerative diseases, but the vast majority of studies have focused specifically on cell death, which is a late stage of disease progression. Recent evidence suggests that synapses are affected long before the onset of clinical symptoms. Our goal is to understand how synapses are adversely affected in neurodegenerative diseases, and test whether reversing this synaptic pathology can prevent or delay neuronal death.